The P2 receptor subtypes P2Y2, P2Y4, P2Y6 and the adenosine receptor subtype A2B are all expressed in human airways. Instillation of ATP, UTP, or UDP into the lungs produces an increase in the mucociliary clearance process in the airway epithelium. This response to extracellular nucleotides is produced by a number of events triggered by activation of one or more P2Y receptors, resulting in an increase in fluid and chloride secretion (P2Y2, P2Y4, and P2Y6), inhibition of sodium absorption (P2Y2, P2Y4, and P2Y6), and increase in mucin secretion (P2Y2 and P2Y4). These events, in concert with an increase in ciliary beat frequency, are responsible for the natural clearance of the airways. See Kellerman, Chest. 121:201S-205S (2002); Knowles, J Clin Invest. 109:571-7 (2002); Leipziger, Am J Physiol Renal Physiol. 284: F419-32 (2003); Kunzelmann, Clin Exp Pharmacol Physiol. 28:857-67(2001); and Schwiebert, Biochim Biophys Acta. 1615:7-32 (2003).
The role of P2Y6 receptors has not been as clearly defined as that of P2Y2 receptors and their agonists due in part to the lack of selective P2Y6 agonists. Stimulation of P2Y6 receptors causes a dose-dependent increase of fluid secretion, chloride secretion and ciliary beat frequency (Morse, Am. J. Physiol. Cell Physiol. 280:C1485-497 (2001)). UDP, the natural agonist of P2Y6 receptors, has lower efficacy promoting mucociliary clearance than agonists of P2Y2 receptors, whether the low efficacy of the natural P2Y6 receptor agonist UDP is due to its metabolic liability is not known.
Mucus clearance is the cornerstone in the innate defense mechanism of the lung against disease produced by inhaled bacteria, viruses, chemicals and particulate material. In several lung diseases such as chronic obstructive pulmonary diseases (COPD), mucus hypersecretion, decreased clearance and inflammation contribute to airflow obstruction, resulting in destructive changes in the pulmonary parenchyma associated with an increase of morbidity and mortality. In these patients, airway clearance therapy is necessary to prevent infection, increase oxygenation and prevent progression of the decline in lung function.